The objective of this project is to determine the mode of transmission of bipolar manic depressive illness in the families of 100 consecutively hospitalized bipolar manic depressive patients. Two independent methods of analysis will be carried out: an analysis of the genetic linkage between the loci for manic depressive illness and glucose-6-phosphate dehydrogenase (G6PD) on the X-Chromosome; and an analysis of family data using newly developed techniques for the testing of the multifactorial (MF) and single major locus (SML) models of transmission. The possibility that there is more than one subform of bipolar manic depressive illness will be investigated by linkage and family analysis on subgroups of subjects defined by age of onset or severity of illness in the probands. Probands and relatives will be interviewed using a structured interview and psychiatric diagnoses will be made using carefully defined criteria. In addition, the G6PD genotype of affected and unaffected family members and probands will be ascertained by analysis of G6PD enzyme activity and polyacrylamide electrophoretic mobility. A powerful method for detecting linkage will be modified in order to accomodate the incomplete penetrance which most likely occurs in this disorder, and will be used to determine whether the loci for bipolar manic depressive illness and G6PD are close to each other on the X-Chromosome. If linkage occurs, then individuals who most probably carry a gene for manic depressive illness and who are unaffected will be compared to their affected relatives in order to ascertain differences which may be responsible for the occurrence of the illness in genetically predisposed individuals.